Two-component supramolecular gels derived from amphiphilic shape-persistent cyclo[6]aramides for specific recognition of native arginine

Article abstract of DOI:10.1002/anie.201407092

A unique supramolecular two-component gelation system was constructed from amphiphilic shape-persistent cyclo[6]aramides and diethylammonium chloride (or triethylammonium chloride). This system has the ability to discriminate native arginine from 19 other

Full text of DOI:10.1002/anie.201407092

Angewandte
Chemie
DOI: 10.1002/anie.201407092
Supramolecular Gels
Two-Component Supramolecular Gels Derived from Amphiphilic
Shape-Persistent Cyclo[6]aramides for Specific Recognition of Native
Arginine**
Youzhou He, Min Xu, Rongzhao Gao, Xiaowei Li, Fengxue Li, Xuedan Wu, Dingguo Xu,*
Huaqiang Zeng, and Lihua Yuan*
Abstract: A unique supramolecular two-component gelation
system was constructed from amphiphilic shape-persistent
cyclo[6]aramides and diethylammonium chloride (or triethyl-
ammonium chloride). This system has the ability to discrim-
inate native arginine from 19 other amino acids in a specific
fashion. Cyclo[6]aramides show preferential binding for the
guanidinium residue over ammonium groups. This specificity
was confirmed by both experimental results and theoretical
simulations. These results demonstrated a new modular
displacement strategy, exploring the use of species-binding
hydrogen-bonded macrocyclic foldamers for the construction
of two-component gelation systems for selective recognition of
native amino acids by competitive host–guest interactions. This
strategy may be amenable to developing a variety of functional
two-component gelators for specific recognition of various
targeted organic molecular species.
ability to adapt to their surroundings. Particularly, multi-
component gelation systems where two or more constructing
species interact through noncovalent or covalent forces to
form a gel have shown significant advantages, such as the
ready adjustment of gel performance and in exquisite micro-
structural tunability,[7] while providing an additional level of
control in the hierarchical assembly process. Two-component
gel systems have been widely investigated with diverse
scaffolds,[8,9] among which comparatively fewer are fabricated
with macrocyclic compounds, such as crown ether,[10] calixar-
ene,[11] porphyrin,[12] cyclodextrin,[13] cucurbituril,[14] pillarar-
ene,[15] and other cyclic species.[16] Some recently reported
macrocycle-based two-component gelation systems did
exhibit stimuli-responsive sol–gel transitions that however
were induced by the competitive binding of guests of different
types in an indiscriminate fashion.[13a,15b]
Shape-persistent aromatic oligoamide macrocycles[17]
have emerged as a new class of host molecules concomitant
with the development of their acyclic analogues.[18] These
macrocycles feature full amide linkages with backbones
enforced by intramolecular hydrogen bonds. Among these
systems, those developed by Gong and co-workers are
particularly intriguing in view of the simplicity of synthesis
and the high-yield production of the circular products.[19] We
recently demonstrated that these highly efficient kinetic
macrocyclization reactions arise from both the hydrogen-
bonded backbones and the remote steric effect.[20] With their
shape-persistent aromatic surfaces, the macrocycles carrying
extra-annular alkyl side chains are prone to self-aggregation
in both polar and nonpolar solvents as a consequence of the
cooperative action of dipole–dipole and p–p stacking inter-
actions.[21] With their correctly arranged amide oxygen atoms
pointing inwards, the near-planar six-residue macrocycles,[22]
dubbed cyclo[6]aramides, have shown highly selective recog-
nition of guanidinium ions,[23] efficient separation of metal
ions,[24] and a high affinity for dialkylammonium salts.[25]
Remarkably, a cyclo[16]aramide with a larger nanosized
cavity could accommodate even a depsipeptide antibiotic
valinomycin.[26] However, these macrocycles have never been
employed as gelators to construct two-component gelation
systems for selective recognition of molecular species.
S
upramolecular gels represent one of the most important
soft materials using noncovalent interactions (hydrogen
bonding, p–p interactions, metal–ligand coordination, van
der Waals forces, and hydrophobic effects) for forming
nanofibrillar structures able to “freeze” solvents in the rigid
gel framework.[1] Their many functional applications of
interest include recognition,[2] drug delivery,[3] tissue engineer-
ing,[4] catalysis,[5] and crystal growth,[6] as a result of their built-
in specific responsiveness toward external stimuli and their
[*] Y. He, M. Xu, R. Gao, X. Li, F. Li, X. Wu, Prof. D. Xu, Prof. L. Yuan
College of Chemistry, Key Laboratory for Radiation Physics
and Technology of Ministry of Education
Sichuan University, Chengdu 610064 (China)
E-mail: lhyuan@scu.edu.cn
dgxu@scu.edu.cn
Dr. H. Zeng
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos, 138669 (Singapore)
[**] This work is supported by the National Natural Science Foundation
of China (21172158, 31170675, 21073125), the Doctoral Program of
the Ministry of Education of China (20130181110023), the National
Science Foundation for Fostering Talents in Basic Research of the
National Natural Science Foundation of China (J1210004 and
J1103315), Open Project of State Key Laboratory of Supramolecular
Structure and Materials (SKLSSM201408) and Open Project of State
Key Laboratory of Structural Chemistry (20140013). The Compre-
hensive Training Platform of Specialized Laboratory, College of
Chemistry, Sichuan University, is acknowledged for NMR and
HRESI-MS analyses.
Protein a-amino acids are considered as fundamental
constituents of a wide variety of biomolecules. In this family,
arginine is essential to the functioning of polypeptides such as
enzymes and antibodies.[27] It also plays an important role as
the precursor for nitric oxide in arginine metabolism.[28]
Despite much progress made in the recognition of amino
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407092.
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Table 1: Minimum gelation concentrations for 1, 1·DEA-HCl, and 1·TEA-
HCl in various organic solvents at 258C.[a]
acids and their derivatives by small neutral molecules and
macrocycles,[27,29] the use of macrocycle-based gels for dis-
tinguishing native or modified amino acids is rather rare.[11b]
There are few examples of 2D planar (or near-planar) shape-
persistent macrocyclic compounds, such as arylene ethynyl-
ene macrocycles and macrocyclic fluoropentamers, that are
able to act as gelators,[30] none of which have demonstrated
any recognition ability for amino acids. Herein, we present
a modularly tunable strategy for constructing supramolecular
two-component gelation systems based on amphiphilic shape-
persistent cyclo[6]aramide 1 and diethylammonium chloride
(DEA-HCl) or triethylammonium chloride (TEA-HCl)
(Figure 1; for synthesis see the Supporting Information),
Entry
solvent
1
1·DEA-HCl
1·TEA-HCl
1
2
3
4
5
6
7
methanol
THF
ethanol
acetonitrile
i-propanol
n-propanol
n-butanol
I
I
I
P
I
0.78
1.08
0.89
1.16
1.30
0.79
0.78
1.29
3.06
1.00
1.27
2.19
0.91
0.90
I
I
[a] [Guest]/[Host] given in (wt%), where the guest molecule is DEA-HCl
or TEA-HCl. P=precipitation, I=insoluble.
methanol was found to be 0.78% in the
presence of DEA-HCl and increases to
1.29% using TEA-HCl (Entry 1, Table 1).
The higher gelation ability of 1 with DEA-
HCl may result from an enhanced binding
of the less sterically crowded cation
+
Et2NH2 of DEA-HCl compared to the
larger Et3NH+ of TEA-HCl through
charge-assisted hydrogen bonds that facili-
tate intermolecular aromatic stacking. The
likely species responsible for gel formation
was revealed by mass spectrometry to be
a 1:1 ratio of the host–guest complex
[1·DEA + H]+ (Figure S16a in the Support-
ing Information). The two-dimensional
NOESY spectrum of a solution of an
equimolar mixture of 1 and DEA-HCl in
a solvent mixture of CD3OD and CDCl3
(4:1, v/v) disclosed correlations between the
signals attributable to the interior aromatic
Figure 1. Two-component gelation systems consisting of amphiphilic cyclo[6]aramide 1 and
DEA-HCl (or TEA-HCl) salts. Alternative cyclo[6]aramides 2–4 failed to undergo gelation in
methanol in the presence of ammonium salts.
and their ability to specifically recognize arginine through
a competitive displacement process. To our knowledge, this
work represents the first example employing two-component
gelation systems based on macrocycles for visual specific
discrimination of organic guests, specifically native amino
acids in this work.
protons of 1 and alkyl protons l or m from DEA-HCl
(Figure S19). No NOE correlations between signals attribut-
able to the exterior aromatic protons and peripheral side
chain protons of 1 and the protons denoted l or m were
detected. In the case of TEA-HCl, similar results were
obtained (see Figures S16b and S18). These results suggest
that alkylammonium ions are bound inside the cavity of
1 instead of locating about the periphery of 1. Note,
molecule 1 is unable to gelate in nonpolar solvents such as
dichloromethane, chloroform, and 1,2-dichloroethane with or
without DEA-HCl or TEA-HCl.
Since the oxygen atoms from both the four TEG ether
side chains and internal amide carbonyl groups in 1 may
interact with ammonium ions, it is possible for one macro-
cyclic molecule to bind more than one alkylammonium ion.
Thus, we first examined the dependence of the gel–sol
transition temperature (Tgel) on different ratios of 1 to
DEA-HCl to determine the stoichiometry of the complex
responsible for gelation in methanol. As shown in Figure 2,
the Tgel values increases rapidly with increasing additions of
DEA-HCl, and reaches a plateau value with after the addition
of 1 equivalent of the ammonium salt. Further additions of
ammonium ions did not lead to a further increase in thermal
stability. In the case of TEA-HCl, a similar trend was
Cyclo[6]aramide 1 was insoluble in methanol, and unable
to form a gel. Simply by mixing DEA-HCl in methanol with 1,
a clear solution formed after heating at circa 658C, and it
turned into a thermoreversible gel within several minutes
upon cooling. Use of TEA-HCl led to a similar gelation result.
In stark contrast to 1, compound 2 with six tetraethylene
glycol (TEG) side chains and 3 (or 4) bearing six alkyl groups
(Figure 1) did not undergo gelation in methanol in the
presence of DEA-HCl or TEA-HCl under identical condi-
tions. This difference in gelation behavior suggests the
important role played by the peripherally located amphiphilic
side chains of 1 (i.e., TEG and alkyl groups) in inducing gel
formation. The results of gelation tests for the ability of 1 to
form gel-phase materials in the presence of the second
component, alkylammonium chloride, are summarized in
Table 1. In general, 1 entraps polar solvents more efficiently
with DEA-HCl as the second component than TEA-HCl. For
example, the minimum gelation concentration (MGC) in
2
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As formation of the gel relies on macrocyclic host–guest
interactions, introduction of another competitive guest to the
two-component gelation system is expected to induce
a change in the supramolecular structure and eventually
may lead to the collapse of the macroscopic gel, possibly
enabling the visual discrimination of guest molecules. It has
been established that cyclo[6]aramides can specifically rec-
ognize guanidinium ions.[23] Thus, the possibility for the
stimuli-specific responses of the two-component gels toward
arginine (specifically the l-form, denoted l-Arg) was first
explored by adding l-Arg (1 equivalent) to a gel formed from
1·DEA-HCl (20 mm) in methanol. When the mixture was
heated to approximately 658C and cooled to room temper-
ature, the gel containing l-Arg collapsed to form an opaque
solution (Figure S23). Interestingly, under the same condi-
tions the gel remains unchanged with the use of 19 other
amino acids (1 equivalent). Thus, specific discrimination of
l-Arg from the other 19 amino acids could be achieved by
direct visual observation of the breakdown of the two-
component gel. It should be further noted that a complete gel
collapse occurred only when l-Lys (2 equivalents) was used.
Even under these conditions, we still observed a striking
difference in gel transformation between l-Arg and l-Lys.
The gel turned into a clear solution upon addition of l-Arg,
but addition of l-Lys produced only an opaque solution
(Figure S24). These results confirm the selective nature of the
gel response toward l-Arg using the amphiphilic cyclo[6]-
aramide, implying that native amino acids bearing a guanidyl
group may be appropriate candidates to compete with
secondary ammonium ions, and give rise to gel collapse.
Although a specific response to l-Arg is now possible, it is
unclear if the selectivity would be retained in the presence of
all the other 19 amino acids, especially when lysine, a com-
petitive binding species, is also present. Therefore, a mixture
consisting of 20 amino acids (1 equivalent of each) was added
to the 1·DEA-HCl gel (20 mm) in methanol and tested with
a heating–cooling procedure. The gel was found to collapse.
In a control experiment, a mixture containing 19 amino acids
(1 equivalent of each) excluding l-Arg failed to cause the gel
to sol transformation, indicating that the specific response
towards l-Arg indicated by collapse of the gel was maintained
in competitive environments. More importantly, the MALDI-
TOF mass spectral experiment with a sample composed of 20
amino acids and 1·DEA-HCl provided strong evidence for the
specific recognition of l-Arg. An intense peak attributable to
the complex [1·Arg + H]+ was observed at m/z 2151.2 (Fig-
ure 3a). This strongly suggests the preference of cyclo[6]-
aramide gel 1 to bind the amino acid l-Arg over the other
amino acids.
Figure 2. Dependence of the gel–sol transition temperature Tgel on the
molar ratio of ammonium salt/cyclo[6]aramide 1 showing saturation at
1:1 stoichiometry in methanol. For the DEA-HCl experiment (red
diamonds), [1]0 was held constant at 7 mm. For the TEA-HCl experi-
ment (black circles), [1]0 was held constant at 12 mm.
obtained, strongly suggesting the formation of a 1:1 host-guest
complex that is responsible for gelation.
Scanning electron microscopy (SEM) images of the the
xerogel superstructures of the two-component gels (1:1
complex) showed the presence of network fibrillar structures
containing dense cross-links with a width of approximately
365 nm (see Figures S8 and S9). Transmission electron mi-
croscopy (TEM) images of the xerogels revealed bundles of
the individual filaments, pointing to a higher level of order
(see Figure S10 and S11). These images indicated that the
two-component gelators formed highly interpenetrated net-
works. To gain further insight into the assembly process
involving the amphiphilic cyclo[6]aramide and alkylammo-
nium ions, the xerogel was prepared from a solution of 1 and
DEA-HCl in methanol, deposited on glass, and was studied
by wide-angle X-ray diffraction (Figure S12). The diffracto-
gram revealed a single sharp peak dominating over the low
angle region at an angle of 2q = 3.38, indicative of columnar
assemblies.[30a,d] A d-spacing of 2.64 nm was calculated from
the angle of this primary diffraction peak. The presence of
three other prominent peaks at 1.53 nm, 1.31 nm, and
pffiffi
pffiffi
1.03 nm, with ratios of d-spacings of about 1:1/ 3:1/2:1/ 7,
indicated that these columns are packed in a hexagonal lattice
in the 1:1 complex 1·DEA-HCl. The reflection around
0.37 nm was attributed to resulting from the corresponding
p–p stacking interactions between the coplanar aromatic
backbones (2q, 20–308).[21,31] Similar results were obtained for
1·TEA-HCl (Figure S13). Thus, the information retrieved
from the wide-angle X-ray diffraction analysis supports the
stacking of the macrocyclic molecules into nanotubular
structures, which is consistent with the observation of very
long fibers from SEM and TEM images. Therefore, it is clear
that a two-component gelation system based on the amphi-
philic cyclo[6]aramide 1 and alkylammonium ions was con-
structed. To our knowledge, there are no other two-compo-
nent gelation systems fabricated from shape-persistent
H-bonded 2D macrocycles through host–guest interactions.
The binding of l-Arg was further validated by the
2D NOESY spectra of a solution containing an equimolar
mixture of 1, DEA-HCl, and l-Arg (each 5 mm) in CD3OD
(see Figure S20). Correlations between the signals attribut-
able to the interior aromatic protons of 1 (denoted i and/or k)
and protons of l-Arg (denoted n or o) were observed. In
contrast, no cross-peaks associated with the interaction of
DEA-HCl and the macrocycle appeared, strongly suggesting
that competitive complexation by arginine occurred within
the cavity of the macrocycle. In other words, arginine can
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not observed. Therefore, it is most likely that the terminal
guanidinium residue of arginine is the binding moiety that
interacts with 1. The 2D NOESY experiment of a solution
containing an equimolar mixture of 1 and DDGC (each
5 mm) in CDCl3 provided further evidence for the interaction
of the guanidinium moiety with 1 and the presence of the
guanidinium ion in the cavity of 1 (Figure S21). The amino
acid lysine (Lys) could be considered as a combination of
dodecylammonium chloride (DDAC) and AME-HCl. From
1H NMR spectroscopy titrations in CD3OD/CDCl3 (11:9, v/v),
binding constants between a nonaggregational cyclo[6]ara-
mide 4 and DDGC, DDAC, DEA-HCl, or AME-HCl were
calculated to be 1.2 ꢀ 105, 6.5 ꢀ 104, 1.8 ꢀ 104, and 5.0 ꢀ 103 mꢀ1
,
respectively (Table S1). Thus, the binding affinities of the
macrocycle towards different guest molecules decrease in the
order of DDGC (guanidinium part of l-Arg) > DDAC
(alkylammonium part of l-Lys) > DEA-HCl > AME-HCl.
Given the fact that the guanidinium moiety is the strongest
binder among all the guests tested and the nonaggregational
macrocycle 4 shares the same number of interior carbonyl
oxygen atoms as 1, the binding constants strongly suggest that
1 should follow a similar binding trend as 4 toward various
guests, that is, l-Arg >l-Lys > DEA-HCl.
To comprehend the recognition event from a microscopic
view, extensive molecular dynamics (MD) simulations were
carried out for three complex systems, specifically 5-arginine,
5-lysine, and 5-diethyl ammonium (DEAH+). In each case,
the guest molecules were found to remain stably around the
cavity (Figure S33). On the basis of the calculated binding
energies, our computational results revealed that the binding
affinity of cyclo[6]aramide for different guests decreases in
the order of l-Arg >l-Lys > DEAH+ (Table S2). Thus, the
results of the calculations provide a partial explanation for the
competitive binding observed between l-Arg and DEAH+ in
the cyclo[6]aramide system.
The two-component gel assembly and recognition event
may involve a two-stage process: a) gel assembly through
host–guest interactions between the alkylammonium guest
and the macrocyclic host 1, and b) collapse of the gel by the
competitive binding of the arginine guest molecule through
proton transfer from alkylammonium to arginine, resulting in
the displacement of the alkylammonium ion from
1 (Figure 4). For the gel hierarchical assembly process,
a mixture containing the amphiphilic cyclo[6]aramide and
DEA-HCl was heated in methanol to afford a clear solution
where the ammonium cation was introduced into the cavity of
the macrocycle by host–guest interactions. Upon cooling,
intermolecular aggregation led to assembled bundles, whose
formation were caused by p–p stacking and van der Waals
forces among side chains. Eventually, a three-dimensional
fibril network was produced with the ability to gelate solvent
molecules. Collapse of the gel occurred when l-Arg was
added, as evidenced by a significant decrease in the average
size of aggregates from 1040.0 nm for a mixture of 1 (5.0 mm)
and DEA-HCl (5.0 mm) in CH3OH/CHCl3 (7:3, v/v) to 8.0 nm
upon addition of 1 equivalent of l-Arg (Figures S14 and S15).
This could be rationalized by the stronger binding capability
and higher basicity of the guest (Arg) molecule that favorably
facilitates proton transfer from the alkylammonium salt. It is
Figure 3. a) MALDI-TOF spectrum of 1 in the presence of DEA-HCl,
and 1 equivalent of each of 20 amino acids (l-Arg, l-Lys, l-His, l-Ala,
l-Asn, l-Ile, l-Leu, l-Gln, l-Met, l-Thr, l-Gly, l-Ser, l-Phe, l-Val, l-Pro,
l-Tyr, l-Trp, l-Asp, l-Cys, and l-Glu), in methanol; b) Competitive
displacement of diethylammonium chloride (DEA-HCl) by l-Arg that
leads to the collapse of the gel.
replace diethylammonium in the cavity of the macrocycle,
a likely determining factor that causes the collapse of the gel
(Figure 3b).These results from 1H NMR spectroscopic
experiments indicated that the amino residue of l-Arg is
protonated through a proton-transfer process from DEA-
HCl, either in the presence or absence of the cyclo[6]aramide
(Figure S17).
To pinpoint the binding site that dominates the recog-
nition process, two model compounds, dodecylguanidinium
chloride (DDGC) and alanine methyl ester hydrochloride
(AME-HCl), were employed to mimic the function of the
guanidinium and the ammonium moieties in the molecule of
l-Arg. The first indication that 1 binds DDGC more tightly
than AME-HCl came from the MALDI-TOF spectra (see
Figure S16). When using an equimolar mixture of DDGC and
the amphiphilic cyclo[6]aramide 1, the highest intensity peak
in the mass spectrum was detected at m/z 2204.2, correspond-
ing to the complex [1·DDGCꢀCl]+. However, when AME-
HCl was used, formation of the complex [1·AME+H]+ was
4
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In summary, this work demonstrated a unique approach to
construct a supramolecular two-component gelation system
based on amphiphilic shape-persistent cyclo[6]aramides and
diethylammonium chloride (or triethylammonium chloride).
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diverse novel organic gelation systems with selective recog-
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Received: July 11, 2014
Revised: August 14, 2014
Published online: && &&, &&&&
Keywords: arginine · host–guest systems ·
.
molecular recognition · oligoamide macrocycles ·
supramolecular gels
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6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Supramolecular Gels
Picking and choosing: A supramolecular
two-component gelation system based
on the amphiphilic cyclo[6]aramidema-
crocycle and diethylammonium chloride
is reported. This system provides a mod-
ularly tunable approach for creating
functional two-component gel systems
for highly specific recognition of l-argi-
nine (l-Arg) from 19 other amino acids by
competitive host–guest interactions.
Y. He, M. Xu, R. Gao, X. Li, F. Li, X. Wu,
D. Xu,* H. Zeng,
L. Yuan*
&&&& — &&&&
Two-Component Supramolecular Gels
Derived from Amphiphilic Shape-
Persistent Cyclo[6]aramides for Specific
Recognition of Native Arginine
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!